Glucagon-like Peptide-1 Receptor Agonists and Thyroid Cancer: Review of Preclinical and Human Data

Preclinical rodent studies showing a dose-dependent increase in thyroid C-cell hyperplasia and neoplasia with Glucagon-like Peptide-1 Receptor Agonists (GLP-1RAs), led the United States Federal Drug Administration to require a boxed warning contraindicating GLP-1RAs for patients with a personal or family history of medullary thyroid carcinoma (MTC) or in patients with Multiple Endocrine Neoplasia syndrome. However, neither primate oncogenicity studies nor patient clinical trials showed C-cell stimulation, calling into question the relevance of rodent models to humans. Indeed, rodents have a high rate of spontaneous thyroid C-cell tumors, a higher number of thyroid C-cells and GLP-1 receptors and use a different pathway from humans in MTC oncogenesis. Although, the majority of meta-analyses of randomized clinical trials and cohort studies using administrative, electronic medical record and/or registry databases report no clear association between GLP-1RA use and thyroid cancer development, pharmacovigilance database studies do demonstrate a positive relationship; however, this association can only be inferred as a possible signal rather than causation and is likely due to notoriety or reporting bias. Additionally, analysis of the overall trends of thyroid cancer incidence in the U.S. since the release of GLP-1RAs for patient use in 2005 show an early increase, probably due to overdiagnosis of papillary carcinoma (PTC); however, the relative proportion of MTC has actually decreased. Because the preponderance of data does not support a causative relationship between GLP-1RA use and MTC (or PTC), we conclude that the need for the boxed warning about the risk of C-cell neoplasia is no longer necessary.